Progress in small-cell lung cancer research
Small-cell lung cancer (SCLC) accounts for about 13-15 per cent of all lung cancer cases, with a high degree of malignity and a negative forecast, with a survival rate of less than 7 per cent over five years. After decades of a treatment platform, the school community has made many breakthroughs in understanding the heterogeneity of SCLC biology and tumours and is expected to bring new hope to people with this difficult disease.
Morbidity and mortality
It is estimated that approximately 250,000 new SCLC patients are added globally each year, resulting in at least 200,000 deaths. Since SCLC is closely associated with high levels of smoking, its global incidence largely reflects smoking habits over time, with a lag of about 30 years. With the implementation of public health measures, such as the promotion of anti-smoking and non-smoking programmes, changes in the composition of cigarettes and the reduction of occupational hazards, the incidence of SCLC has steadily declined since the late 1980s. It should be noted that, although the incidence of SCLC has declined over the past decades, the overall survival rate of patients (OS) remains extremely low.
Risk factors
SCLC is closely related to excessive tobacco exposure. Among SCLC patients, 94 per cent of males and 93.9 per cent of females have a history of smoking, and the risk ratio of former smokers and current smokers to SCLC (OR) is 12.9 (95 per cent CI, 9.79 ~17.1) and 42.0 (95 per cent CI, 21.7 ~81.2) respectively. It is noteworthy that exposure to second-hand smoke is also a carcinogenic factor in SCLC. However, the proportion of ever smokers among the Asian population appears to be higher, with more than 10 per cent of those who have never smoked.
Indoor radon exposure and air pollution may be the second largest risk factor for SCLC and the main risk factor for non-smokers. Alpha radiation from radon can damage and cause mutation in the lung membrane cells. At the same time, air pollutants (e.g. particles with a diameter of less than 10 μm and nitrogen dioxide) have direct carcinogenic effects, especially SCLC and scorpular lung cancer.
Screening
It is now clear that low-dose CT screening can reduce the risk of non-small cell lung cancer (NSCLC) mortality; however, in lung cancer screening experiments, a significant proportion of SCLC cases were inter-stage cancer (i.e. diagnosed within one year of the negative results of the screening); only about one third of all SCLC patients were detected through screening. Furthermore, the vast majority of the cases detected in these screenings are at an advanced stage. As a result, annual low-dose CT screening has not significantly improved the survival or treatment of SCLC. Considering that low-dose CT screening still reveals a significant number of early NSLCs (and very few early SCLCs), while the screening of SCLC is much less effective than that of NSLC, screening of all at-risk populations on the basis of evidence-based guidance is still necessary.
Prevention
Given the close causal link between smoking and SCLC, smoking cessation is the most effective measure to prevent the disease. In fact, the risk of contracting SCLC after smoking quits is gradually reduced. In addition, smokers tend to have higher survival rates than those who continue to smoke, when diagnosed as SCLC.
The United States Environmental Protection Agency recommends radon testing for all dwellings below the third floor and protective measures for dwellings with radon content of 4 pg/L or more.
In the 1980s, for the first time, researchers observed morphological differences in SCLC cell systems, revealing at first glance the existence of the SCLC subtypes: “classic” and “variant” subtypes. Recent studies have found that SCLC subtypes are not necessarily defined by mutation of genes, but by certain transcribing factors and inflammation characterizations. The Board ‘ s deadlines and extended periods are divided into subtypes based on the high expression and inflammation characteristics of ASCL1, NEURD1 and POU2F3. These new sub-forms are important clinically, as they are relevant to the treatment response and there are significant differences in morphology, growth properties, genetic modification and prognosis. SCLC sub-types include ASCL1 (SCLC-A sub-type), NEUROD1 (SCLC-N), POU2F3 (SCLC-P) and YAP1 (SCLC-Y). The A and N subtypes usually have higher levels of neuroendocrine marker expression, while the P and Y subtypes have lower neuroendocrine levels.
Of the 437 MCLC real-world multi-group assessments, 35.7 per cent, 17.6 per cent, 6.4 per cent, 21.1 per cent and 19.2 per cent were of A, N, P and Y sub-types or mixed sub-groups, respectively.
Sub-specific molecular maps and clinical biomarkers can assist in developing new target-oriented treatment strategies. For example, the high expression of DLL3 in SCLC-A tumours is a clinical development target for various SCLC therapies. Tarlatamab is a two-specific T-cell connector that connects the DLL3 and CD3 molecules of the T-cell surfaces of the tumour cell, so that T-cells can be precisely directed and activated to kill the tumour cell. The 2nd DeLphi-301 trial showed that among previously treated SCLC patients, tarlatamab showed a high tumour-resistant activity (with an objective relief of 40%) and the median PFS for the 10 mg and 100 mg groups was 4.9 and 3.9 months respectively. Based on these encouraging results, in May 2024, the United States Food and Drug Administration (FDA) accelerated the approval of tarlatamab (10 mg) for both ES-SCLC patients and platinum patients or for patients with post-chemical conditions.
Similarly, BCL-2 is overexpressed in SCLC-A, and members of the BCL-2 family, such as BCL-XL, who are resistant to death, are often overexpressed in SCLC, and may also be the target of treatment for this malignant tumor. Various BCL-2 inhibitors have been approved globally. In the SCLC pre-clinical model, the combined inhibition of BCL-2 or BCL-XL and MML1 is well synergistic, but the failure to improve the clinical efficacy of standardized treatment in clinical trials raises the question of how best to apply these preclinical findings to SCLC.
The SCLC-N subtype is closely related to MYC overexpression. Although the treatment for MYC has not yet been directly evaluated among the SCLC patients, SCLC-N patients may benefit from SCLC treatment programmes for overexploitation of MYC, such as CHK1 inhibitors and polyethylene diolide deaminolasy. In addition, various MYC direct inhibitors have been developed and tested in preclinical studies.
The SCLC-P subtype is characterized by POU2F3. In a pre-clinical study, SCLC cells expressing POU2F3 were more dependent on transfer factors SOX9 and ASCL2 and IGF1R, suggesting that they might be sensitive to TKI drugs targeting the recipient. Analysis of other drug responses shows that SCLC-P cells are sensitive to PARP inhibitors. The potential value of IGF-1R inhibitors and PARP inhibitors will need to be tested in future for SCLC-Pal patients.
The SCLC-Y cell system is resistant to Iriditian and BCL-2 inhibitors. In addition, the integrity of the RB1 expression in these cells means that they may be sensitive to CDK4/6 inhibitors. Another pre-clinical study showed that SCLC-Y subcells were sensitive to mTOR and PLK inhibitors. Several pre- and clinical studies have further found that SCLC-Y sub-types are rich in genetic characteristics associated with cytotoxic T-cells, NK-cells and jammer-dependent signals, suggesting that immunosuppressants may have a therapeutic effect on the sub-type.
Surgery
Surgery has been excluded from SCLC treatment for decades, mainly because of disappointing results of surgical-based random clinical trials in the 1970s and 1990s. Nevertheless, for patients with a very early stage of disease (T1~2N0M0), the three-year survival rate is still above 50% after pulmonary folic removal + after lymphomy. In addition, the recent test of pro-rated matching shows that the long-term survival rate of patients with a later stage of the disease for surgical treatment is encouraging. The current NCCN guide recommends pulmonary ectomy for all SCLCs with a clinical period of I~IIA (T1~T2N0M0) and after the operation, assisted chemotherapy. Pulmonary anatomy (preferably pulmonary folicectomy), gender (a significant increase in the survival rate of female patients) and R0 excision are predictors of long-term benefits. In the near future, negative detection of post-operative tumour cells or ct DNA may be important for pre-evaluation.
Chemotherapy and release
Full-body chemotherapy is the main method of treatment in SCLC, and platinum-type DNA combinations (e.g. shunply or carpenter) and amphiposteric inhibitors (e.g. toupper or ilitecon) are currently the preferred chemotherapy programmes for SCLC patients. This combination therapy has significant efficacy, and it is safe to use it either alone or in conjunction with other whole-of-body drugs (e.g., immunotherapy) or partial treatment (e.g., leaching or surgery).
The life cycle of chemotherapy varies from disease to disease. The use of four cycles of platinum/carpenter and itopoporium is recommended for the Directorate’s deadline SCLC, including patients who have undergone pulmonary surgery. Patients for a wide range of periods can receive up to six cycles of chemotherapy based on post-reaction and tolerance after four cycles.
In addition to full-body chemotherapy, retrofitting also plays a key role in the treatment of SCLC patients as part of a definitive or palliative treatment. Serialized chemotherapy is one of the standard treatments for patients of limited duration (under N3, M0), while extensive treatment for SCLC patients consists mainly of post-one-line treatments for chest consolidation. In addition, regional lymphoma dymphoma dysentery patients treated with surgical treatment are recommended for treatment, which can be carried out in sequence and in parallel with chemotherapy.
Immunization treatment
Broad term SCLC. The SCLC treatment standard has not changed in any meaningful way for decades. The results of three rounds of the IMPower133 trial show that the first-line standard treatment combined with the Atricorn stand alone could significantly increase the median PFS and OS by 0.9 months and 2 months respectively, with a higher survival rate of 1 year and 1.5 years. In 2019, FDA established a new milestone for SCLC treatment by authorizing the single-initiative antiplatinum two-pharmaceutical treatment line. The three CASPIAN tests used different PD-L1 inhibitors and the results were similar to those observed in IMPow133. The single anti-polytherapy in Valyu increased significantly by 2.7 months compared to the median OS in the individual chemotherapy group.
It is noteworthy that the median OS in both studies, which has been extended by approximately two months, does not seem to be high, but the median value does not explain the whole problem. A look at the end of the survival curve shows that adding immunosuppressants to platinum-type drugs can increase the patient ‘ s survival rate by about threefold over the three years.
Bureau term is SCLC. In a 1/2 trial, the monolithic anti-consolidation treatment of Pablo was very resilient and active. However, during the two random STIMULI experiments, the immunotherapy consolidation treatment did not improve PFS.
ADRIATIC is a random 3-step test that includes SCLC patients with the I-III Bureau deadline and is treated for consolidation of the variyote (n = 264) or placebo (n = 266) respectively after the completion of the free chemotherapy. Medium-term analysis shows that the median of OS in the single resistance group of Deviryu was about 56 months, compared to 33 months in the placebo group. The median PFS for the single resistance group in Devereau was 17 months, while the placebo group was 9 months. The first demonstration of the benefits of immunotherapy can also be found among SCLC patients of limited or non-transferable duration.
Resume SCLC treatment.
The follow-up of the entire body of SCLC depends on the drugs used in the first-line treatment and the absence of a period after the initial treatment has ended. According to the NCCN Guide, where the period between initial treatment and recurrence is more than six months (sensitive diseases), re-treatment is recommended using the original or similar platinum programme; if no disease interval is at least 3-6 months (hospital or drug-resistant diseases), re-treatment may be considered using the original or similar platinum programme. If it is no longer possible to use the original drug, the expansion of the isomerase 1 inhibitor to the stupor is the preferred drug for second-line treatment.
Navulillo and Pablo Monovalent, who had received accelerated FDA approval to use patients who had undergone platinum chemotherapy and at least one of the other front lines for post-disease treatment. However, in the subsequent test of proof, neither drug reached its main end point, and FDA and the manufacturer revoked the certificates of adaptation of Navulillo and Pablo C.S.L. patients. Nevertheless, in some cases, where there has been no previous use of immunotherapy, experimental use outside the label within clinical trials may be considered, based on individualized considerations. Treatment, clinical trials and other chemotherapy programmes may also be a difficult SCLC option.
Small cell lung cancer.
